CZ20023269A3 - Process for preparing (+) -cis-sertraline - Google Patents

Abstract

The present invention is directed to (+)-cis-sertraline hydrochloride and methods of preparation. The present invention also includes processes for making sertraline having a cis/trans ratio greater than 3:1, greater than or equal to 8:1, or between about 8:1 and about 12:1, from the Schiff base of sertralone, sertraline-1-imine.

Description

Process for the preparation of (+) - cis-sertraline

Technical field

The invention relates to a process for the preparation and purification of (+) - cis-sertraline.

BACKGROUND OF THE INVENTION

Sertraline hydrochloride, (1S-cis) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride of formula

sertraline hydrochloride is the active ingredient in Zoloft, a drug approved by the US Department of Food and Drug for the treatment of depression, obsessive-compulsive disorder and panic disorder.

01-2658-02-English · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Cl sertralon

U.S. Patent 4,536,518 describes the synthesis of sertraline hydrochloride from sertralone. This method of synthesizing sertraline hydrochloride from sertralone involves two steps. First, the sertralone is condensed together with methylamine in the presence of an acid catalyst to form the sertralone Schiff base, i.e. sertraline-1-imine.

sertraline 1-imine

This imine, or Schiff's base, is subsequently reduced to sertraline. The reduction process of U.S. Pat. No. 4,536,518 involves two hours of hydrogenation of the sertraline-1-imine concentrate at room temperature and above 10% Pd / C catalyst in a hydrogen atmosphere (101.3 Pa). The product is a racemic mixture of cis and trans diastereomers (hereinafter "(±) - cis / trans-sertraline") in a ratio of about 3: 1. This hydrogenation step, if not carefully controlled, can bring with it a variety of contaminants, including

01-2658-02-English * Dechlorinated by-products. One very problematic group of by-products is the dechlorinated sertraline derivatives. It is therefore desirable to provide a hydrogenation method that would reduce or eliminate the amount of dechlorinated sertraline by-products.

Purification of cis-sertraline from (±) -cis / trans-sertraline, as described in U.S. Pat. No. 4,536,518, is relatively complex and requires costly multiple recrystallization, wherein the (±)-cis / trans-sertraline thus produced has cis / trans ratios lower than 3: 1. It is therefore desirable to develop a method for the initial production of cis / trans-sertraline base from sertraline-1-imine with cis / trans ratios higher than 3: 1. It is also desirable to develop a simple, inexpensive and efficient purification of (+) - cis - sertraline from (±) - cis / trans-sertraline base or from (±) - cis / trans-sertraline hydrochloride.

SUMMARY OF THE INVENTION

The invention relates to a process for preparing (±) -sertraline having a cis / trans ratio greater than about 3: 1, comprising the step of hydrogenating sertraline-1-imine at a temperature of at least about 40 ° C using a catalyst selected from the group consisting of palladium and platinum. In the methods of the invention, suitable catalysts are palladium on carbon, palladium on graphite, palladium on carbon paste, and PtO ₂ .

The invention also relates to a cis / trans ratio between the step of hydrogenating the at least about 40 catalyst. In processes for the preparation of (±) -sertraline of approximately 8: 1 and 12: 1 which sertraline-1-imine at a temperature using the palladium according to the invention are suitable

01-2658-02-Palladium on carbon, palladium on graphite and palladium on carbon paste.

The invention also relates to a process for the preparation of (+) - cis-sertraline hydrochloride, comprising the step of reacting an optically active selective precipitant with a (±) sertraline base having a cis / trans ratio greater than 3: 1.

The invention also relates to a process for the preparation of (+) - cis-sertraline substantially free of dechlorinated by-products, the process comprising the step of catalytic hydrogenation of sertraline-1-amine using PtO ₂ as a catalyst.

The invention also relates to a process for preparing (+) - cis-sertraline hydrochloride from (±) -sertraline hydrochloride with a cis / trans ratio greater than 3: 1, comprising the steps of: preparing (±) -sertraline by adding an aqueous base to (±) sertraline hydrochloride having a cis / trans ratio greater than 3: 1; resolution of the (±) sertraline thus prepared; and isolating (+) - cis-sertraline hydrochloride.

The invention also relates to a process for the preparation of (+) - cis-sertraline hydrochloride from (±) -sertraline hydrochloride, comprising the steps of: preparing (±) -sertraline by adding a solid base to (±) -sertraline hydrochloride; resolution of the (±) sertraline thus prepared; and isolating (+) - cis-sertraline hydrochloride.

The invention with sertraline from (±) sertraline byproducts of sertraline, about 1%, also relates to a process for preparing (+) - cis (+) - sertraline base, wherein the base has a very low dechlorinated content, for example lower than or alternatively,

01-2658-02-Eng

dechlorinated sertraline by-products not detectable by conventional methods, the method comprising the steps of: preparing (±) -sertraline by adding a solid base to (±) -sertraline hydrochloride; resolution of the (±) sertraline thus prepared; and isolating (+) - cis-sertraline hydrochloride.

The invention provides a novel process for the preparation of (±) - cis / trans-sertraline having a cis / trans ratio greater than about 3: 1 by hydrogenation of sertraline-1-imine. It also provides a novel process for the preparation of sertraline from Schiff's base sertralone, i.e., sertraline-1-imine. The methods of the invention provide high cis / trans ratios of (±) -cis / trans-sertraline. It is also expected that the methods of the invention will result in less impurities and by-products than the prior art methods. The hydrogenation methods of the invention also result in a very low content of dechlorinated by-products of sertraline.

According to the invention, sertraline is prepared from the Schiff base of sertralone, i. from sertraline-1-imine. Sertraline-1-imine can be prepared by the method of U.S. Patent 4,536,518, the contents of which are incorporated herein by reference. Sertraline-1-imine is dissolved in an organic solvent such as tert-butyl methyl ether (MTBE), tetrahydrofuran (THF), toluene, ethanol, isopropanol, n-butanol, ethyl acetate, acetone, methanol or mixtures thereof, and catalytically hydrogenated under heating in the presence of hydrogen gas. Suitable catalysts include platinum and palladium. In a preferred embodiment of the invention, the catalyst is palladium. Preferably, the palladium catalyst is palladium on carbon, palladium on graphite, or palladium on carbon paste where the metal loading is

01-2658-02-Ce of palladium about 5% to 10% based on dry weight.

More preferably, the catalyst is 10% Pd / C (w / w). In another preferred embodiment of the invention, the catalyst is platinum. More preferably, the platinum catalyst is PtO ₂ .

In the methods of the invention, the reaction mixture is heated to at least about 40 ° C. The reaction mixture can be heated on a heated jacket. Preferably, the reaction mixture is heated and maintained at about 40 ° C to about 80 ° C. More preferably, the reaction mixture is heated and maintained at about 40 ° C to about 60 ° C.

Discard after completion of the reaction

-sertraline.

solvent

The isolated reaction mixture is filtered, and the (±) -cis / trans (±) -cis / trans-sertraline of the invention is isolated having a very low content of dechlorinated sertraline by-products. Dechlorinated sertraline by-products herein refer to sertraline derivatives wherein one or both of the chlorine atoms in 3,4-phenyl is replaced by hydrogen. In which the catalyst used is (±) -cis / trans-sertraline cis / trans of about 12: 1, which is a significant increase over the cis / trans ratio of about 3: 1 seen in the prior art. In an embodiment of the invention wherein palladium on graphite in ethanol at about 40 ° C is used as the catalyst in the hydrogenation of sertraline-1-amine, it has an isolated

The sertraline cis / trans ratio of about 12: 1 according to the invention, when palladium on graphite is used as the catalyst, ethanol is the preferred solvent. In embodiments of the invention where palladium on charcoal is used as the catalyst, the preferred solvents are targets. butyl methyl ether and toluene. In the embodiments where at hydrogenation ---- ---- ^{J 1 J} ~ 'methods of the invention, palladium, an insulated ratio of about 8: 1 to (±) -cis / trans-sertraline embodiment l -amine

The tert-butyl methyl ether at about 40 ° C uses palladium as the catalyst, the dechlorinated sertraline by-products content is less than about 1%.

In the methods of the invention where PtO ₂ is used as a catalyst, no dechlorinated sertraline byproducts were detected by isolated methods in isolated (±) - cis / trans-sertraline. Preferably, the isolated (±) -cis / trans-sertraline is substantially free of dechlorinated sertraline by-products. The isolated (±) -cis / trans-sertraline has a cis / trans ratio greater than about 3: 1. Preferably, the cis / trans ratio is about 4: 1. Table 1 provides additional data and reaction conditions regarding the hydrogenation of sertraline-1-imine.

In the processes for preparing (+) - cis-sertraline hydrochloride of the invention from the crude (±) -cis / trans-sertraline base, the (±) -cis / trans-sertraline base is dissolved in a suitable organic solvent such as toluene, isopropanol, ethanol, tert-butyl methyl ether, methanol, n-butanol or ethyl acetate, and the solution is warmed to a temperature such as about 50 ° C. Resolution of the (±) - cis / trans-sertraline base is facilitated by the use of an optically active selective precipitant. An optically active selective precipitant, such as (? -) - mandelic acid, (L) -mandelic acid, (+) - 10-camphorsulfonic acid or (-) - 10-camphorsulfonic acid, is added to the reaction mixture, and the mixture is then heated to reflux temperature. (D) -mandelic acid and (L) -mandelic acid are preferred; with (R) - mandelic acid being more preferred. The mixture is cooled to room temperature and stirred, preferably for about 2 hours or until completion of the reaction. The completion of the reaction can be monitored by methods known in the art. Filtration of the reaction mixture followed by drying affords the crude (+) - sertraline precipitant,

01-2658-02-English preferably raw (+) - sertraline mandelate . This crude (+) - sertraline precipitant is further purified by recrystallization in a suitable organic solvent. The preferred solvent is ethanol and isopropanol, with ethanol being more preferred.

The recrystallized (+) - sertraline precipitant is dissolved in a suitable organic solvent such as toluene, ethyl acetate, isopropanol, tert-butyl methyl ether or hexane. The precipitated sertraline solution is rinsed with an aqueous basic solution, such as 10% sodium hydroxide (NaOH), 10% potassium hydroxide (KOH), and the like, to remove a selective precipitant such as mandelic acid. The organic phase of the solution is further washed with water and the (+) - sertraline base isolated by evaporation of the solvent. The (+) - sertraline base is dissolved in a suitable organic solvent, such as ethanol, and the solution is cooled. The cooled organic solution is then acidified with hydrochloric acid while maintaining the reaction temperature at approximately 10 ° C to facilitate the formation of (+) - cis-sertraline hydrochloride. The reaction mixture is subsequently stirred at room temperature for a suitable period of time, for example for about 2 h, to precipitate (+) - cis-sertraline hydrochloride. The completion of the reaction can be monitored by conventional methods. Form V of (+) - cis-sertraline hydrochloride is isolated by filtration and dried.

Sertraline hydrochloride Form V is disclosed in U.S. Patent No. 5,248,699, the contents of which are incorporated herein by reference. U.S. Patent No. 5,248,699 characterizes sertraline hydrochloride Form V by single crystal X-ray analysis, powder X-ray diffraction, infrared spectroscopy, and differential scanning calorimetry. Form V

The sertraline hydrochloride resulting from the practice of the invention can be characterized by its powder X-ray diffraction pattern. Basic peaks can be observed ····

0 ··

0 0 0 · 0 0

0000 ··

approximately at 5.2 ± 0.2 , io / 4 ± 0.2, 11, 0 + 14.3 ± 0.2, 16.5 ± 0.2, 17.3 ± 0,2, 18.4 + 0.2, 19, 1 + 19.7 ± 0.2, 20.9 ± 0.2, 22.0 ± 0,2, 23.2 ± 0.2, 23, 6 + 25.5 ± 0.2, 26, 0 ± 0.2 a 29.1 ± 0.2 degrees 2Θ

IR

The spectrum of sertraline hydrochloride Form V prepared by the process of the invention is characterized by the following bands: 773 cm ^-1 , 822 cm ^-1 , 1012 cm ^-1 , 1032 cm ^-1 , 1054 cm ^-1 ,

1133 cm ¹ , 132 8 cm ¹ , 15 62 cm ^-1 and 1590 cm ¹

The methods of preparing (+) - cis-sertraline of the invention allow the direct production of precipitated sertraline or sertraline mandelate from the sertraline racemate resulting from the hydrogenation, i.e. reduction, of sertraline-1-imine. This improved, efficient and economical purification is possible when the sertraline racemate has a relatively high cis / trans ratio, such as about 8: 1 to about 12: 1, as well as when the content of dechlorinated sertraline by-products is low, e.g. less than about 1%. The methods of the invention have successfully eliminated the need for several purification steps prior to the selective precipitation of (+) - cis-sertraline with an optically active selective precipitant.

The invention also provides an alternative process for preparing (+) - cis-sertraline hydrochloride. Crude (±) -cis / trans-sertraline having a cis / trans ratio greater than 3: 1 can be treated with hydrochloric acid to prepare crude (±) -cis / trans-sertraline hydrochloride having a cis / trans ratio greater than 3: 1 . This crude (±) -cis / trans-sertraline hydrochloride having a cis / trans ratio greater than 3: 1 is dissolved in an organic solvent, at least partially

Water-insoluble, such as ethyl acetate, isopropanol, tert-butyl methyl ether, n-butanol, isobutanol and toluene, or in a non-basic, water-miscible solvent, such as isopropanol , and rinsing with a suitable aqueous basic solution, such as 10% sodium hydroxide solution, 10% potassium hydroxide solution and the like, to form a (±) - cis / trans-sertraline base.

The organic and aqueous phases are then separated. Resolution of the (±) -cis-sertraline base is accomplished using an optically active selective precipitant. An optically active selective precipitant, as described above, for example (D) -mandelic acid, is directly added to the organic phase containing (±)-cis / trans-sertraline. The crude (+) - sertraline precipitant is then crystallized directly from this organic solution. Thus, the process of the invention eliminates the need to recrystallize the sertraline hydrochloride racemate before adding a selective precipitant such as (D) -mandelic acid. (+) - cis-Sertraline hydrochloride is then prepared from crystallized crude (+) - sertraline precipitant as described above. For example, the recrystallized (+) - sertraline precipitant is dissolved in a suitable organic solvent such as toluene, ethyl acetate, isopropanol, tert-butyl methyl ether or hexane. The sertraline precipitate solution is rinsed with an aqueous basic solution such as 10% sodium hydroxide (NaOH), 10% potassium hydroxide (KOH) and the like to remove a selective precipitant such as mandelic acid. The organic phase of the solution is further washed with water and the (+) - sertraline base isolated by evaporation of the solvent. The (+) - sertraline base is dissolved in a suitable organic solvent, such as ethanol, and the solution is cooled. The cooled organic solution was added

01-2658-02-English. ....

. 1 · · · ·. Subsequently, it is acidified with hydrochloric acid while maintaining the reaction temperature at approximately 10 ° C. to form (+) - cis-sertraline hydrochloride. The reaction mixture is subsequently stirred for a suitable period of time, for example about 2 h, at room temperature, whereby precipitation of (+) - cissertraline hydrochloride is achieved. Completion of the reaction can be monitored by conventional methods. Form V of (+) - cis-sertraline hydrochloride is isolated by filtration and dried.

(±) - cis / trans -Strtraline hydrochloride can also be recrystallized once and dissolved in a suitable organic solvent such as ethanol, isopropanol, methanol, n-butanol and isobutanol. Ethanol is preferred. Optical resolution is performed by adding a solid base such as potassium hydroxide, sodium hydroxide, sodium carbonate (Na 2 CO 3) and sodium bicarbonate (NaHCO 3) / directly to the sertraline hydrochloride racemate solution. The salts are then removed by a suitable method, for example by filtration. An optically active selective precipitant, as described above, for example (? -) mandelic acid, is added to the organic solution, and (+) - cis-sertraline precipitant, for example (+) - cis-sertraline mandelate, precipitates directly from the of this organic solution. The resulting crude (+) - cis-sertraline precipitant is recrystallized. Recrystallized (+) - cis-sertraline precipitant, for example (+) - cis-sertraline mandelate, is dissolved in an organic solvent and the mandelic acid is removed with a base, for example by rinsing the organic solution with aqueous basic solutions, for example 10% to 20% hydroxide solution. sodium hydroxide (NaOH) or 10% to 20% potassium hydroxide (KOH) solution. The (+) - cis-sertraline free base is isolated, which is dissolved in a suitable organic solvent and treated with hydrochloric acid. (+) - cis-Sertraline hydrochloride precipitates «··· ** · * ··

01-2658-02-English ·

In the form of crystals and dried to give Form V of (+) - cis-sertraline hydrochloride.

The methods of the invention provide a fast and efficient method for carrying out very sensitive optical resolutions. Table 3 provides additional data and reaction conditions regarding optical resolution. Improved efficient and economical purification is possible if the sertraline racemate has a relatively high cis / trans ratio, for example about 8: 1 to 12: 1. The methods of the invention have successfully eliminated the need for several purification steps prior to the selective precipitation of (+) - cis-sertraline with an optically active selective precipitant.

The following examples are illustrative only, and are not intended to limit the scope of the invention as set forth in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Step 1: Preparation of sertraline-1-imine (Schiff's base)

Sertralone (100 g) was dissolved in toluene (1400 mL) and the solution thus obtained was cooled to 0-5 ° C. Methylamine gas (38.7 g) was bubbled through the solution while maintaining the temperature of the solution at 0-5 ° C. To the above solution was added dropwise while maintaining the temperature below 10 ° C TClCl (20 mL). The reaction mixture was allowed to warm to room temperature and then stirred at room temperature for 3 h. After completion of the reaction, T102 was removed by filtration and the filtrate was evaporated to dryness. Fixed

01-2658-02-Eng

the substance obtained after evaporation was sertraline-1-imine (101.17 g; 100% yield).

Step 2: Preparation of (+) - cis / trans-sertraline (sertraline racemate) free base

A suspension of sertraline-1-imine (Schiff's base) (10 g) in tert-butyl methyl ether (MTBE) (270 mL) was hydrogenated in the presence of Pd / C (10% loading) at 40 ° C and a hydrogen pressure of 101.3 Pa. After about 5 h, the reaction was complete. Filtration of the reaction mixture through a cellite pad and evaporation of the solvent gave (±) - cis / trans-sertraline free base (sertraline racemate, free base) (10 g) as an oil.

Table 1 - Hydrogenation of sertraline-1-imine

Solvent Catalyst Metal load Temperature Ratio cis / trans racemate MTBE Pd / C 10% Deň: 32 ° C 9: 1 Toluene Pd / C 10% 60 ° C 8: 1 EtOH Pd / graphite 5% Deň: 32 ° C 12: 1 MTBE Pd / C, paste 10% Deň: 32 ° C 9: 1 MTBE PtO ₂ Deň: 32 ° C > 3: 1

Step 3: Preparation of crude (+) - sertraline mandelate

The sertraline free base racemate (75.6 g) was dissolved in ethanol (760 mL) and the solution was heated to approximately 50 ° C. (R) - Mandelic acid (37.6 g) was added and the solution was heated to reflux temperature. The mixture was cooled to room temperature and stirred for 3 h. Filtration, rinsing with ethanol and subsequent drying at approximately 60 ° C gave the crude product

(+) - sertraline mandelate in 83.7% yield (40.7 g), 94.6%

SS-sertraline and 3.01% RR-sertraline.

The optical purity of (+) - sertraline mandelate was determined by chiral HPLC.

Step 4: Preparation of (+) - sertraline mandelate crystals

Crude (+) - sertraline mandelate (40 g) was crystallized from ethanol (920 mL). The hot solution was treated with activated charcoal, then filtered and cooled to room temperature. The obtained solid was collected by filtration and washed with ethanol. After drying, crystals of (+) - sertraline mandelate were obtained in 82.8% yield (31.95 g). 99.0% of SS-sertraline was detected across the board and no RR-sertraline was detected.

Step 5: Preparation of Form V (+) - Sertraline Hydrochloride

The crystals of crude (+) - sertraline mandelate in toluene were partitioned between 10% aqueous NaOH and toluene. The organic solution was washed with water and the solvent was evaporated to dryness to give (+) - sertraline base (6.9 g). A solution of (+) - sertraline base (3.7 g) in ethanol (18.5 mL) was acidified with hydrogen chloride gas while maintaining the temperature at approximately 10 ° C. Then the mixture was cooled to room temperature and stirred for 2 h. After filtration, washing the solid with ethanol and drying, Form V (+) - sertraline hydrochloride ((+) - sertraline HCl) was obtained (3.16 g, 82.7% yield). 99.6% of SS-sertraline was detected across the board and no RR-sertraline was detected.

01-2658-02-English · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···· 4 9 4 4 4 4 4 5

The procedure of steps 3 to 5 was performed five times as described above. Table 2 includes the specific conditions and results of these five experiments.

Table 2

Input Type of sample. Preparing buns Yield (%) 1 (±) -sertraline base H ₂ / Pt ₂ 61.9 (+) - raw mandelate toluene, 60 ° C, rt (rt), 2 h 41.7 (+) -Mergy raw ethanol (EtOH), reflux, m.p. 2 h 85.5 (+) - sertraline · HCl EtCH / HCl (g) 83.1 total yield 18.3 2 (±) -sertraline base H ₂ / Fd / C 81.2 (+) - raw mandelate Toluene, 10 vol, 60 ° C, rt, 2 h 45.2 (+) - crystallization mandelate I EtCH, reflux, r.t. 2 h 86.2 (+) -mandelate crystallization II EtCHab, reflux, r.t. 2 h 87.2 (+) - sertraline-HCl EtCH abs./HCl (g) approximately 90 total yield 24.9 3 (+) - sertraline base H ₂ / Dd / C, ΕΕ, 40 87.7 (+) -Mergy raw Toluene, 10 vol, 60 ° C, rt, 2 h 41.2 (+) -Mergate crystallization EtOH abs., Reflux, m.p. 2 h 88.2 (+) - sertraline · HCl approximately 90 total yield 28.75 4 (+) - sertraline base H ₂ / M / C 83 (+) - raw mandelate Toluene, 10 vol, 60 ° C, rt, 2 h 40 (+) - crystallization mandelate EtCH abs., Reflux, r.t. 2 h 86.7 (+) - sertraline · HCl EtCH abs./HCl (g) 71.7 total yield 20.6 5 (±) -sertraline base H ₂ / Dd / C, toluene, 60 ° C 78 (+) - raw mandelate Toluene, 10 vol, 60 ° C, rt, 2 h 44.2 (+) - crystallization mandelate EtCH abs., Reflux, r.t. 2 h 87.5 (+) - sertraline · HCl EtCH abs./HCl (g) 80.1 total yield 24.2

01-2658-02-English • · 0 ·

Example 2

Optical resolution (±) -Sertraline hydrochloride (5 g) was dissolved in ethanol (20 mL) and powdered KOH (85%) was added to the solution. The suspension was stirred at room temperature for 2.5 h. After stirring, the solids were removed by filtration and D- (-) - mandelic acid (2.66 g) was added to the solution. Precipitation occurred and stirring was continued for 24 h. (+) - Sertraline mandelate was isolated by filtration, rinsed with ethanol, and after drying to give 2.70 g of (+) - sertraline mandelate.

The optical purity of (+) - sertraline mandelate was determined by chiral HPLC methods. Table 3 provides additional data and reaction conditions regarding the optical resolution of sertraline. In Table 3, the% enantiomers of RR represents the percentage area of PP-enantiomer determined by chiral HPLC; Chiracel OD-H, 250 x 4.6 nm, 5pm, column temperature 5 ° C. In Table 3, yield (%) is the optical resolution yield relative to% of the actually obtained SS-enantiomer of sertraline hydrochloride against the theoretical assumption of the amount of SS-enantiomer of sertraline hydrochloride obtained. The yield was calculated from the optical purity value of the obtained (±) -sertraline hydrochloride. In Table 3, the test (%) is the percentage of the SS enantiomer of sertraline hydrochloride as determined by the chiral HPLC method and using the SS enantiomer of sertraline hydrochloride as a standard.

01-2658-02-Eng

Table 3 - Optical resolution

Input Solvent Base % RR- -Enantiomer Yield (%) Test (%) 1 1-Propanol 20% aq, NaOH 2.4 83.4 99 2 n-Butanol 20% aq, NaOH 2.7 81.9 96.1 4 Ethyl acetate 20% aq, NaOH 1.06 76, 9 5 Toluene 20% aq, NaOH 2.2 75, 8 6 terc.Butyl- methyl ether 20% aq, NaOH 22.9 85.1 7 Ethanol KOH powder, 85% 4, 6 79.3 89.3

01-2658-02-Eng

Claims (8)

PATENT CLAIMS A process for the preparation of (±) -sertraline having a cis / trans ratio greater than about 3: 1, comprising the step of hydrogenating sertraline-1-imine at a temperature of at least about 40 ° C using a catalyst selected from the group consisting of palladium and platinum. The method of claim 1, wherein the temperature is between about 40 ° C and about 80 ° C. The process of claim 1 wherein the catalytic hydrogenation is carried out in an organic solvent selected from the group consisting of ethanol, tetrahydrofuran, toluene, isopropanol, n-butanol, ethyl acetate, acetone, methanol and tert-butyl methyl ether, and mixtures thereof. 4. The method of claim 1 wherein said catalyst is selected from the group consisting of palladium on carbon, palladium on graphite, palladium on carbon paste, and PtO _second The method of claim 4, wherein the (±) sertraline has a dechlorinated sertraline by-product content of less than about 1%. »· · · 01-2658-02-Eng The process of claim 4, wherein the catalyst is PtO27. The method of claim 6, (±) -sertraline is substantially by-products of sertraline. characterized by being free of dechlorinated 8. The process of claim 6 wherein the catalytic hydrogenation is carried out in an organic solvent selected from the group consisting of ethanol, tetrahydrofuran, toluene, isopropanol, n-butanol, ethyl acetate, acetone, methanol and tert-butyl methyl ether, and mixtures thereof. The method of claim 3; se by that the solvent is ethanol. 10. Method the catalyst is according to claim palladium na 9; graphite. se by that 11. Method the solvent is according to claim 3, characterized by: tert.butylmethyl ether. se by that 12. Method the catalyst is according to claim palladium na 11; activated carbon. se by that 01-2658-02-English · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 13. The process of claim 3 wherein the solvent is toluene. 14. The process of claim 13 wherein the catalyst is palladium on charcoal. 15. The process of claim 1 wherein the cis / trans ratio is between about 8: 1 and about 12: 1 and the catalyst is palladium. The method of claim 15, wherein the temperature is between about 40 ° C and about 80 ° C. 17. The process of claim 15 wherein the catalyst is selected from the group consisting of palladium on carbon, palladium on graphite, and palladium on carbon paste. 18. The method of claim 17, wherein the sertraline product is less than about 1%. 19. The process of claim 17 wherein the catalyst is palladium on activated carbon, wherein the metal loading of palladium is about 5 wt. % to about 10 wt. 01-2658-02-English ······················································ · · · ························· 20. The process of claim 15 wherein the catalytic hydrogenation is carried out in an organic solvent selected from the group consisting of ethanol, tetrahydrofuran, toluene, isopropanol, n-butanol, ethyl acetate, acetone, methanol and tert-butyl methyl ether, and mixtures thereof. 21. Way according to claim 20, characterized se by that the solvent is tert.butylmethylether. 22nd Way according to claim 20, characterized se by that the solvent is ethanol. 23. Way according to claim 20, characterized se by that the solvent is toluene. 24. Way according to claim 15, characterized se by that the cis / trans ratio is approximately 12: 1. The method of claim 24, wherein the temperature is between about 40 ° C and about 80 ° C. 26. The process of claim 24 wherein the catalyst is selected from the group consisting of palladium on carbon, palladium on graphite, and palladium on carbon paste. • ···· 44 44 ·· ·· ···· 01-2 658-02-What! . * *. Jí. * Eat 4 · ··· ······················· 27. The method of claim 26 wherein the content of dechlorinated sertraline by-products is less than about 1%. The method of claim 27, wherein the catalyst is palladium on graphite, wherein the palladium loading is about 5 wt. % to about 10 wt. 29. The process of claim 24 wherein the catalytic hydrogenation is carried out in an organic solvent selected from the group consisting of ethanol, tetrahydrofuran, toluene, isopropanol, n-butanol, ethyl acetate, acetone, methanol and tert-butyl methyl ether, and mixtures thereof. 30. The process of claim 27 wherein the solvent is ethanol. A process for the preparation of (+) - cis-sertraline hydrochloride from (±) -sertraline base, comprising the steps of: a) reacting the optically active selective clotting agent with (±) -sertraline base, wherein the (±) -sertraline base has a cis / trans ratio greater than about 3: 1, to form (+) - cis-sertraline of the clotting agent; 9 9 9 9 »9 9 ·· 9 of the precipitating agent into the solution to form a base for the reaction 01-2658-02-Eng 99 9 b) reacting (+) - sertraline with a basic (+) - sertraline base; c) introducing (+) - sertraline hydrochloric acid to form a precipitate of (+) - cis-sertraline hydrochloride; and d) isolating (+) - cis-sertraline hydrochloride. and 32. The method of claim 31 wherein the content of dechlorinated sertraline by-products is less than about 1%. 33. The method of claim 31, wherein the cis / trans ratio is between about 8: 1 and about 12: 1. 34. The process of claim 31 wherein step a) is carried out in an organic solvent selected from the group consisting of toluene, isopropanol, ethanol, tert-butyl methyl ether, methanol, n-butanol or ethyl acetate. The method of claim 31, wherein the basic solution is selected from the group consisting of aqueous sodium hydroxide solution and aqueous potassium hydroxide solution. 01-2658-02-English · to · this * to · this · to · · 36. A process for the preparation of (+) - cis-sertraline hydrochloride from (±) -sertraline hydrochloride having a cis / trans ratio greater than 3: 1, comprising the steps of: (a) preparing (±) -sertraline base by adding an aqueous base to (±) -sertraline hydrochloride with a cis / trans ratio greater than 3: 1; b) resolving the (±) sertraline base thus prepared to form a (+) - sertraline base; c) reacting the (+) - sertraline base with hydrochloric acid to form a precipitate of (+) - cis-sertraline hydrochloride; and d) isolating (+) - cis-sertraline hydrochloride. The method of claim 36, wherein step b) further comprises the following steps: a) reacting the optically active selective precipitant with a (±) -sertraline base having a cis / trans ratio greater than about 3: 1 to form (+) - cis-sertraline of the precipitant; and b) reacting the (+) - sertraline precipitant with a basic solution to form a (+) - sertraline base. The method of claim 36, wherein the dechlorinated by-side content is less than about 1%. characterized by the sertraline product it is 01-2658-02-Eng 0000 0 0 000 000 0 0 0000 0000 0000 · 0000 00 00 39. The process of claim 36 wherein (+) sertraline hydrochloride is dissolved in an organic solvent that is substantially immiscible with water. 40. The process of claim 39 wherein the organic solvent is selected from the group consisting of ethyl acetate, isopropanol, n-butanol, isobutanol, tert-butyl methyl ether, and toluene. 41. The method of claim 36, wherein the aqueous basic solution is selected from the group consisting of sodium hydroxide solution and potassium hydroxide solution. 42. A process for preparing (+) - cis-sertraline hydrochloride from (±) -sertraline hydrochloride, comprising the steps of: a) preparing a (±) -sertraline base by adding a solid base to (+) - sertraline hydrochloride; b) resolving the (±) sertraline base thus prepared to form a (+) - sertraline base; c) reacting the (+) - sertraline base with hydrochloric acid to form a precipitate of (+) - cis-sertraline hydrochloride; and d) isolating (+) - cis-sertraline hydrochloride. 43. The method of claim 42, wherein step b) further comprises the following steps: 01-2658-02-«· ·» • * 4 4 4 9 9 4 4 9 9 4 4 4 4 4 9 4 Reacting an optically active selective precipitant with a (±) sertraline base having a cis / trans ratio greater than about 3: 1 to form (+) - cis-sertraline of the precipitant; and b) reacting (+) - sertraline with a basic solution on a base. a precipitating agent to form (+) - sertraline 44. The method of claim 42, wherein the content of dechlorinated sertraline by-products is less than about 1%. 45. The method of claim 42, wherein the (±) sertraline hydrochloride solvent. is dissolved in organic 46. The process of claim 45 wherein the organic solvent is selected from the group consisting of ethanol, isopropanol, methanol, n-butanol, and isobutanol. 47. The process of claim 42 wherein the solid base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.